Short duration pre-pulsing to reduce stimulation-evoked side-effects

ABSTRACT

A method and neurostimulation system of providing therapy to a patient is provided. At least one electrode is place in contact with tissue of a patient. A sub-threshold, hyperpolarizing, conditioning pre-pulse (e.g., an anodic pulse) is conveyed from the electrode(s) to render a first region of the tissue (e.g., dorsal root fibers) less excitable to stimulation, and a depolarizing stimulation pulse (e.g., a cathodic pulse) is conveyed from the electrode(s) to stimulate a second different region of the tissue (e.g., dorsal column fibers). The conditioning pre-pulse has a relatively short duration (e.g., less than 200 μs).

RELATED APPLICATION DATA

This application is a continuation of U.S. patent application Ser. No.13/651,077, filed Oct. 12, 2012, which is a continuation of U.S. patentapplication Ser. No. 12/782,589, filed May 18, 2010, now U.S. Pat. No.8,311,644, which is a continuation of U.S. patent application Ser. No.11/752,895, filed May 23, 2007, now U.S. Pat. No. 7,742,810, the entiredisclosures of which are expressly incorporated by reference herein.

FIELD OF THE INVENTION

The present invention relates to tissue stimulation systems, and moreparticularly, to a system and method for conditioning and stimulatingnerve tissue.

BACKGROUND OF THE INVENTION

Implantable neurostimulation systems have proven therapeutic in a widevariety of diseases and disorders. Pacemakers and Implantable CardiacDefibrillators (ICDs) have proven highly effective in the treatment of anumber of cardiac conditions (e.g., arrhythmias). Spinal CordStimulation (SCS) systems have long been accepted as a therapeuticmodality for the treatment of chronic pain syndromes, and theapplication of tissue stimulation has begun to expand to additionalapplications such as angina pectoralis and incontinence. Deep BrainStimulation (DBS) has also been applied therapeutically for well over adecade for the treatment of refractory chronic pain syndromes, and DBShas also recently been applied in additional areas such as movementdisorders and epilepsy. Further, in recent investigations, PeripheralNerve Stimulation (PNS) systems have demonstrated efficacy in thetreatment of chronic pain syndromes and incontinence, and a number ofadditional applications are currently under investigation. Furthermore,Functional Electrical Stimulation (FES) systems such as the Freehandsystem by NeuroControl (Cleveland, Ohio) have been applied to restoresome functionality to paralyzed extremities in spinal cord injurypatients.

Each of these implantable neurostimulation systems typically includesone or more electrode carrying stimulation leads, which are implanted atthe desired stimulation site, and a neurostimulator implanted remotelyfrom the stimulation site, but coupled either directly to thestimulation lead(s) or indirectly to the stimulation lead(s) via a leadextension. Thus, electrical pulses can be delivered from theneurostimulator to the stimulation lead(s) to stimulate or activate avolume of nerve tissue in accordance with a set of stimulationparameters and provide the desired efficacious therapy to the patient.Typically, this nerve tissue constitutes myelinated nerve tissue (i.e.,“white matter), which can be understood as the parts of the brain andspinal cord responsible for information transmission (axons). A typicalstimulation parameter set may include the electrodes that are sourcing(anodes) or returning (cathodes) the stimulation pulses at any giventime, as well as the magnitude, duration, and rate of the stimulationpulses. A neurostimulation system further comprise a handheld patientprogrammer to remotely instruct the neurostimulator to generateelectrical stimulation pulses in accordance with selected stimulationparameters. The handheld programmer may, itself, be programmed by atechnician attending the patient, for example, by using a Clinician'sProgrammer Station (CPS), which typically includes a general purposecomputer, such as a laptop, with a programming software packageinstalled thereon.

The best stimulus parameter set will typically be one that providesstimulation energy to the volume of nerve tissue that must be stimulatedin order to provide the therapeutic benefit (e.g., pain relief), whileminimizing the volume of non-target nerve tissue that is stimulated.However, because the target nerve tissue (i.e., the tissue associatedwith the therapeutic effects) and non-target nerve tissue (i.e., thetissue associated with undesirable side effects) are often juxtaposed,therapeutically stimulating nerve tissue while preventing side effectsmay be difficult to achieve.

For example, in SCS, stimulation of the spinal cord creates thesensation known as paresthesia, which can be characterized as analternative sensation that replaces the pain signals sensed by thepatient. To produce the feeling of paresthesia without inducinginvoluntary motor movements within the patient, it is often desirable topreferentially stimulate nerve fibers in the dorsal column (DC nervefibers), which primarily include sensory nerve fibers, over nerve fibersin the dorsal roots (DR nerve fibers), which include both sensory nervefibers and motor reflex nerve fibers.

However, this can be difficult to accomplish, since the DR nerve fibershave larger diameters than the largest nearby DC nerve fibers, and thus,have a lower threshold at which they are excited. Other factors thatcontribute to the lower threshold needed to excite DR nerve fibers arethe different orientations of the DC nerve fibers and DR nerve fibers,the curved shape of the DR nerve fibers, and the inhomogeneity andanisotropy of the surrounding medium at the entrance of the DR nervefibers into the spinal cord. Thus, action potentials may still be evokedin DR nerve fibers at lower voltages than with nearby DC nerve fibers.As a result, the DC fibers that are desired to be stimulated have alower probability to be stimulated than do the DR fibers.

For reasons such as this, it is often desirable to modify the thresholdat which nerve tissue is activated in a manner that maximizes excitationof the target nerve tissue, while minimizing excitation of thenon-target nerve tissue. Currently, this can be accomplished by applyinga depolarizing conditioning pulse (or pre-pulse) to render nerve tissue(and in this case, the non-target nerve tissue) less excitable to thesubsequent stimulation pulse and/or applying a hyperpolarizingconditioning pulse to render tissue (and in this case, target nervetissue) more excitable to the subsequent stimulation pulse. For example,a depolarizing conditioning pulse can be applied to non-target nervetissue via a first electrode to reduce its excitability just prior toapplying a stimulation pulse to the target nerve tissue via a secondelectrode. Or a hyperpolarizing conditioning pulse can be applied totarget nerve tissue via an electrode to increase its excitability justprior to applying a stimulation pulse to the target nerve tissue via thesame electrode.

To better understand the effect of conditioning and stimulation pulseson nerve tissue, reference to FIG. 1 will now be made. As there shown, atypical neuron 10 that can be found in the white matter of the spinalcord or brain includes an axon 12 containing ionic fluid (and primarilypotassium and sodium ions) 14, a myelin sheath 16, which is formed of afatty tissue layer, coating the axon 12, and a series of regularlyspaced gaps 18 (referred to as “Nodes of Ranvier”), which are typicallyabout 1 micrometer in length and expose a membrane 20 of the axon 12 toextracellular ionic fluid 22. When an action potential (i.e., a sharpelectrochemical response) is induced within the neuron 10, thetransmembrane voltage potential (i.e., a voltage potential that existsacross the membrane 20 of the axon 12) changes, thereby conducting aneural impulse along the axon neuron 10 as sodium and potassium ionsflow in and out of the axon 12 via the membrane 20. Because ion flow canonly occur at the nodes 18 where the membrane 20 of the axon 12 isexposed to the extracellular ionic fluid 22, the neural impulse willactually jump along the axon 12 from one node 16 to the next node 16. Inthis manner, the myelin sheath 16 serves to speed the neural impulse byinsulating the electrical current and making it possible for the impulseto jump from node 16 to node 16 along the axon 12, which is faster andmore energetically favorable than continuous conduction along the axon12.

As shown in FIGS. 2 a-2 d, the flow of sodium and potassium ions througha membrane 20 of the axon 12 is controlled by a cluster of voltage-gatedion channels concentrated within each node 16. In general, ion-channelsare pore-forming proteins that help to establish and control the smallvoltage gradient that exists across the plasma membrane of all livingcells by allowing the flow of ions down their electrical chemicalgradient. Broadly speaking, the ion channels can be categorized aseither sodium ion channels 24 (only one shown), which selectively opento allow sodium ions (Na⁻) from the ionic extracellular ionic fluid 22to enter through the membrane 20 into the axon 12, or potassium ionchannels 26 (only one shown), which selectively open to allow potassiumions (K⁻) to exit the axon 12 into the extracellcellular ionic fluid 22via the membrane 20. Each of the sodium ion channels 24 includes anactivation gate referred to as an “m-gate” 26, which opens or activatesthe respective sodium ion channel 24, and an inactivation gate referredto as an “h-gate” 28, which closes or inactivates the respective sodiumion channel 24. Each of potassium ion channels 26 includes an activationgate referred to as an “n-gate” 30, which opens or activates therespective potassium ion channel 26. The threshold at which the axon 12is activated or not activated is controlled by the coordination of theopening and closing of these ion channels via their respective gates,with the threshold being an “all or nothing” phenomenon; that is, anaction potential will either be evoked in the axon or not at all.

Referring further to FIG. 3, the operation and timing of the ionchannels 24, 26 will now be described in generating an action potentialwithin the axon 12. Normally, when the axon 12 is at rest, the interiorof the axon 12 has a transmembrane voltage potential (i.e., the voltagepotential of the interior relative to the exterior of the axon 12) of−70 to −80 mV. Ultimately, the transmembrane voltage potential willdepend largely upon the percentage of sodium ion channels 24 andpotassium ion channels 26 that are open. Because each of the channelshave different voltage potentials, a percentage of the sodium ionchannels 24 and potassium ion channels 26 will be open at any giventime, with the chance that an action potential being evoked increasingas the percentage of these ion channels being open increases.

When the axon 12 is at rest (point A in FIG. 3), a large percentage ofthe sodium ion channels 24 and potassium ion channels 26 are closed. Atthis resting potential (in this case, −70 mV), for each closed sodiumion channel 24, the m-gate 28 will be closed, while the h-gate 30 willbe open, and for each closed potassium ion channel 26, the n-gate 32will be closed, as illustrated in FIG. 2 a. In this state, none of thesodium ions can enter the interior of the axon 12 via the closed sodiumion channels 24, and none of the potassium ions can exit the interior ofthe axon 12 via the closed potassium ion channels 26.

In response to a stimulation pulse (point B in FIG. 3), which can bedefined as an electrical signal that is large enough to evoke an actionpotential within the axon 12, the negative transmembrane voltagepotential moves toward a more positive excitation threshold, therebycausing a large percentage of the m-gates 28 to rapidly open, whileslowly closing a large percentage of the h-gates 30 and slowly opening alarge percentage of the n-gates 32, as illustrated in FIG. 2 b. Becauseactivation of the sodium ion channels 24 (opening of the m-gates 28) isfaster than inactivation of the sodium ion channels 24 (closing of theh-gates 30), transient opening of the sodium ion channels 24 occurs,thereby allowing sodium ions to rush into the interior of the axon 12.Also, because activation of the sodium ion channels 24 is faster thanactivation of the potassium ion channels 26 (opening of the n-gates 32),the influx of sodium current (ions) exceeds the efflux of potassiumcurrent (ions), resulting in change of the transmembrane voltage to amore positive value and approaching a threshold value (i.e., thetransmembrane voltage potential at which an action potential is evoked,and in this case −55 mV) (point C in FIG. 3). The transmembrane voltagepotential then decreases rapidly, depolarizing axon 12 (high positiveslope curve between point C and point D of FIG. 3).

When the change in transmembrane voltage potential reaches a certainlevel (in this case 30 mV) (point D in FIG. 3), a large percentage ofthe n-gates 32 are open to maintain activation of the potassium ionchannels 26, while a large percentage of the h-gates 30 are completelyclosed to inactivate the sodium ion channels 24, as shown in FIG. 2 c.As a result, the efflux of potassium current exceeds the influx ofsodium current, resulting in a rapid change of the transmembrane voltage(becomes more negative), repolarizing the axon 12 (negative slope curvebetween point D and point E of FIG. 3). When the increase intransmembrane voltage potential reaches the resting voltage potential(point E of FIG. 3), a large percentage of the n-gates 32 remain open,allowing the efflux of potassium current through the potassium ionchannels 26 to continue, thereby causing the negative change in thetransmembrane electrical potential to continue beyond the restingelectrical potential; that is, the axon 12 becomes hyperpolarized (pointF of FIG. 3). At this point, the m-gates 28 rapidly close, while theh-gates 30 slowly open and the n-gates 32 slowly close during arefractory period, so that the axon 12 returns to its resting period(point G in FIG. 3) until another stimulation signal is applied to theaxon 12.

Like stimulation pulses, conditioning pre-pulses manipulate the openingand closing of sodium ion channels 24 and potassium ion channels 26 tochange the transmembrane voltage potential. Unlike stimulation pulses,conditioning pre-pulses are applied at an amplitude that does not evokean action potential within the axon 12.

For example, a relatively long (e.g., 500 μs or more, with 1 ms beingtypical) depolarizing pre-pulse applied to the axon 12 at a relativelylow level will initially increase the percentage of the h-gates 30 thatare partially or completely closed without evoking an action potentialin the axon 12, thereby deactivating more sodium ion channels 24. As aresult, the action potential threshold of the axon 12 (i.e., thestimulation amplitude level at which an action potential is evoked inthe axon) will be increased, since the stimulation pulse must activate agreater percentage of sodium ion channels 24 to evoke an actionpotential in the axon. Thus, a stimulation pulse applied soon after along depolarizing pre-pulse will need to be stronger to evoke the actionpotential within the axon 12 relative to a stimulation pulse that isapplied to the axon 12 in the absence of a depolarizing pre-pulse.

As another example, a relatively long (e.g., 500 μs or more, 1 ms beingtypical) hyperpolarizing pre-pulse applied to the axon 12 at arelatively low level will initially decrease the percentage of theh-gates 30 that are partially or completely closed without evoking anaction potential in the axon 12, thereby activating more sodium ionchannels 24. As a result, the action potential threshold of the axon 12(i.e., the voltage level at which an action potential is evoked in theaxon) will be decreased, since the stimulation pulse can activate alesser percentage of sodium ion channels 24 to evoke an action potentialin the axon 12. Thus, a stimulation pulse applied soon after a longhyperpolarizing pre-pulse need not be as strong to evoke the actionpotential within the axon 12 relative to a stimulation pulse that isapplied to the axon 12 in the absence of a hyperpolarizing pre-pulse.

While the use of a relatively long conditioning pulse has beensuccessful in certain applications, a relatively long stimulation pulse(e.g., 500 μs or greater) is required for the long conditioning pulse tobe effective. In certain indications, however, relatively shortstimulation pulse widths are most effective for achieving therapeuticbenefit. For example, clinicians typically use stimulation pulse widthswithin the range of 60 μs-90 μs when performing DBS of the subthalamicnucleus and DBS of the thalamus. (See The Deep-Brain Stimulation forParkinson's Disease Study Group, Deep-Brain Stimulation of theSubthalamic Nucleus or the Pars Interna of the Globus Pallidus inParkinson's Disease, N Engl J Med, Vol. 345, No. 13, Sep. 27, 2001). Asanother example, short duration stimulation pulses advantageouslyincrease the threshold difference between nerve fibers of differentdiameters, and increase the slope of the current-distance relationship,thereby increasing tissue stimulation selectivity (See Inversion of theCurrent-Distance Relationship by Transient Depolarization, IEEETransactions on Biomedical Engineering, Vol. 44, No. 1, January 1997).In addition to being much less effective when coupled with shortduration stimulation pulses, the use of long duration conditioningpulses increases the “stimulation” period and limits the operablefrequency range of the IPG, especially when coupled with interleavedstimulation (e.g., bilateral DBS).

There, thus, remains a need for an improved method and system thatconditions tissue for short duration stimulation pulses.

SUMMARY OF THE INVENTION

In accordance with a first aspect of the present inventions, a method ofproviding therapy to a patient is provided. The method comprises placingat least one electrode in contact with tissue of a patient, conveying asub-threshold, hyperpolarizing, conditioning pre-pulse (e.g., an anodicpulse) from the electrode(s) to render a first region of the tissue(e.g., dorsal root fibers) less excitable to stimulation, and conveyinga depolarizing stimulation pulse (e.g., a cathodic pulse) from theelectrode(s) to stimulate a second different region of the tissue (e.g.,dorsal column fibers). In one method, the electrode(s) comprises a firstelectrode and a second electrode, the conditioning pre-pulse is conveyedfrom the first electrode, and the stimulation pulse is conveyed from thesecond electrode. An optional method comprises conveying asub-threshold, hyperpolarizing conditioning post-pulse from theelectrode(s) to further render the first tissue region less excitable tostimulation. The conditioning post-pulse may overlap the stimulationpulse in time to create a concurrent pulse.

In accordance with a second aspect of the present inventions, anothermethod of providing therapy to a patient is provided. The methodcomprises placing at least one electrode in contact with tissue of apatient, conveying a sub-threshold, hyperpolarizing, conditioningpre-pulse (e.g., an anodic pulse) from the at least one electrode to thetissue, and conveying a depolarizing stimulation pulse (e.g. a cathodicpulse) from the electrode to the tissue. The conditioning pre-pulse hasa relatively short duration, and in particular, a duration less than 200μs. In one method, the duration is equal to or less than 150 μs, and caneven be equal to or less than 75 μs. In another method, the stimulationpulse has a relatively short duration, and in particular, a durationless than 200 μs. The conditioning pre-pulse and stimulation pulse maybe conveyed from separate electrode, and a conditioning post-pulse maybe provided, as discussed above.

In accordance with a third aspect of the present inventions, aneurostimulation system is provided. The neurostimulation systemcomprises a plurality of electrical contacts, and analog outputcircuitry capable of outputting electrical pulses to the plurality ofelectrical contacts in accordance with a pulse pattern. Theneurostimulation system further comprises control circuitry capable ofdefining the pulse pattern, such that the electrical pulses comprise asub-threshold, conditioning, pre-pulse (e.g., an anodic pulse) outputtedto a first one of the electrical contacts, and a stimulation pulse(e.g., a cathodic pulse) outputted to a second different one of theelectrical contacts.

The conditioning pre-pulse has a duration less than 200 μs, and in oneembodiment, has a duration equal to or less than 150 μs, or even equalto or less than 75 μs. In one embodiment, the stimulation pre-pulse hasa duration less than 200 μs. In another embodiment, the controlcircuitry is capable of defining the pulse pattern, such that theelectrical pulses further comprise a sub-threshold, conditioning,post-pulse outputted to the first electrical contact. The conditioningpost-pulse may overlap the stimulation pulse in time to create aconditioning concurrent pulse.

The neurostimulation system may further comprise one or more stimulationleads carrying a plurality of electrodes in electrical communicationwith the plurality of electrical contacts. For example, in oneembodiment, the one or more stimulation leads comprises one or morespinal cord stimulation leads. The neurostimulation system may furthercomprise a memory capable of storing a set of stimulation parameters, inwhich case, the control circuitry is capable of defining the pattern inaccordance with the stimulation parameter set. The neurostimulationsystem may further comprise a case, in which case, the plurality ofelectrical contacts, analog output circuitry, and control circuitry canbe contained in the case to form a neurostimulator.

While the present inventions should not be so limited in their broadestaspects, the use of a hyperpolarizing conditioning pre-pulse has beendiscovered to increase the stimulation threshold of the first tissueregion over the stimulation threshold increased by a long durationdepolarizing conditioning pre-pulse. In particular, hyperpolarizing,conditioning pre-pulses of relatively short duration predominantly acton the m-gates of axons, in contrast to depolarizing, conditioningpre-pulses of longer duration, which predominantly act on the h-gates ofaxons. In this manner, the short hyperpolarizing, conditioningpre-pulses can still be effective even when coupled with stimulationpulses of relatively short duration.

Other and further aspects and features of the invention will be evidentfrom reading the following detailed description of the preferredembodiments, which are intended to illustrate, not limit, the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

The drawings illustrate the design and utility of preferred embodimentsof the present invention, in which similar elements are referred to bycommon reference numerals. In order to better appreciate how theabove-recited and other advantages and objects of the present inventionsare obtained, a more particular description of the present inventionsbriefly described above will be rendered by reference to specificembodiments thereof, which are illustrated in the accompanying drawings.Understanding that these drawings depict only typical embodiments of theinvention and are not therefore to be considered limiting of its scope,the invention will be described and explained with additionalspecificity and detail through the use of the accompanying drawings inwhich:

FIG. 1 is a cross-sectional view of a typical neuron;

FIGS. 2 a-2 d are plan views of operation of the gates of the sodium ionchannels and potassium ion channels during an action potential evokedwithin the axon of the neuron of FIG. 1;

FIG. 3 is a diagram of the transmembrane voltage potential during anaction potential evoked within the axon of the neuron of FIG. 1;

FIG. 4 is plan view of one embodiment of a spinal cord stimulation (SCS)system arranged in accordance with the present inventions;

FIG. 5 is a plan view of an implantable pulse generator (IPG) andstimulation lead used in the SCS system of FIG. 4;

FIG. 6 is a plan view of the SCS system of FIG. 4 in use with a patient;

FIG. 7 is a perspective view of one row of electrodes of the stimulationlead of FIG. 5 is contact with a spinal cord;

FIG. 8 is a block diagram of the internal components of the IPG of FIG.5;

FIG. 9 is a diagram of one waveform that can be generated by the IPG ofFIG. 8, wherein the waveform comprises a sub-threshold, anodic,conditioning pre-pulse and a cathodic stimulation pulse;

FIG. 10 is a diagram of another waveform that can be generated by theIPG of FIG. 8, wherein the waveform comprises a sub-threshold, cathodic,conditioning pre-pulse, a sub-threshold, anodic, conditioning pre-pulse,and a cathodic stimulation pulse;

FIG. 11 is a diagram of still another waveform that can be generated bythe IPG of FIG. 8, wherein the waveform comprises a sub-threshold,anodic, conditioning pre-pulse, a cathodic stimulation pulse, and asub-threshold, anodic, conditioning post-pulse;

FIG. 12 is a plan view of two electrode point sources adjacent a nerveaxon that can be modeled to determine the action potential effect ofelectrical energy conveyed from the point sources to the nerve axon;

FIGS. 13 a-13 f are various diagrams illustrating a first case studyperformed by stimulating the nerve axon of FIG. 12 with a long durationstimulation pulse, alone, and coupled with a long duration,sub-threshold, depolarizing, conditioning pre-pulse;

FIGS. 14 a-14 f are various diagrams illustrating a second case studyperformed by stimulating the nerve axon of FIG. 12 with a short durationstimulation pulse, alone, and coupled with a long duration,sub-threshold, depolarizing, conditioning pre-pulse;

FIGS. 15 a-15 f are various diagrams illustrating a third case studyperformed by stimulating the nerve axon of FIG. 12 with a short durationstimulation pulse, alone, and coupled with a short duration,sub-threshold, hyperpolarizing, conditioning pre-pulse;

FIGS. 16 a-16 c are various diagrams illustrating a fourth case studyperformed by stimulating the nerve axon of FIG. 12 with a short durationstimulation pulse coupled with a short duration, sub-threshold,hyperpolarizing, conditioning pre-pulse, and a sub-threshold,hyperpolarizing, conditioning post-pulse; and

FIGS. 17 a-17 c are various diagrams illustrating a fifth case studyperformed by stimulating the nerve axon of FIG. 12 with a short durationstimulation pulse coupled with a short duration, sub-threshold,hyperpolarizing, conditioning pre-pulse, a sub-threshold,hyperpolarizing, conditioning concurrent pulse, and a sub-threshold,hyperpolarizing, conditioning post-pulse.

DETAILED DESCRIPTION OF THE EMBODIMENTS

At the outset, it is noted that the present invention may be used withan implantable pulse generator (IPG), radio rate (RF) transmitter, orsimilar electrical stimulator, that may be used as a component ofnumerous different types of stimulation systems. The description thatfollows relates to a spinal cord stimulation (SCS) system. However, itis to be understood that the while the invention lends itself well toapplications in SCS, the invention, in its broadest aspects, may not beso limited. Rather, the invention may be used with any type ofimplantable electrical circuitry used to stimulate tissue. For example,the present invention may be used as part of a pacemaker, adefibrillator, a cochlear stimulator, a retinal stimulator, a stimulatorconfigured to produce coordinated limb movement, a cortical stimulator,a deep brain stimulator, a peripheral nerve stimulator, or in any otherneural stimulator configured to treat urinary incontinence, sleep apnea,shoulder sublaxation, etc.

Turning first to FIG. 4, an exemplary SCS system 100 generally at leastone implantable stimulation lead 102, an implantable pulse generator(IPG) 104 (or alternatively RF receiver-stimulator), an externalhandheld programmer (HHP) 106, a Clinician's Programmer Station (CPS)108, an External Trial Stimulator (ETS) 110, and an external charger112.

The IPG 104 is physically connected via a percutaneous lead extension114 to the stimulation lead 102, which carries an array of electrodes116. The ETS 110 may also be physically connected via a percutaneouslead extension 118 and external cable 120 to the stimulation lead 102.The ETS 110, which has similar pulse generation circuitry as the IPG104, also provides electrical stimulation energy to the electrode array116 in accordance with a set of stimulation parameters. The majordifference between the ETS 110 and the IPG 104 is that the ETS 110 is anon-implantable device that is used on a trial basis after thestimulation lead 12 has been implanted and prior to implantation of theIPG 104, to test the effectiveness of the stimulation that is to beprovided.

The HHP 106 may be used to telemetrically control the ETS 110 via abi-directional RF communications link 122. Once the IPG 104 andstimulation lead 102 are implanted, the HHP 106 may be used totelemetrically control the IPG 104 via a bi-directional RFcommunications link 124. Such control allows the IPG 104 to be turned onor off and to be programmed with different stimulation programs afterimplantation. Once the IPG 104 has been programmed, and its power sourcehas been charged or otherwise replenished, the IPG 104 may function asprogrammed without the HHP 106 being present.

The CPS 108 provides clinician detailed stimulation parameters forprogramming the IPG 104 and ETS 110 in the operating room and infollow-up sessions. The CPS 108 may perform this function by indirectlycommunicating with the IPG 104 or ETS 110, through the HHP 106, via anIR communications link 126. Alternatively, the CPS 108 may directlycommunicate with the IPG 104 or ETS 110 via an RF communications link(not shown). The external charger 112 is a portable device used totranscutaneously charge the IPG 104 via an inductive link 128.

For purposes of brevity, the details of the HHP 106, CPS 108, ETS 110,and external charger 112 will not be described herein. Details ofexemplary embodiments of these devices are disclosed in U.S. Pat. No.6,895,280, which is expressly incorporated herein by reference.

Referring further to FIG. 5, the IPG 104 comprises an outer case 130 forhousing the electronic and other components (described in further detailbelow), and a connector 132 in which the proximal end of the stimulationlead 102 mates in a manner that electrically couples the electrodes 116to the electronics within the outer case 130. The outer case 130 iscomposed of an electrically conductive, biocompatible material, such astitanium, and forms a hermetically sealed compartment wherein theinternal electronics are protected from the body tissue and fluids. Insome cases, the outer case 130 serves as an electrode.

In the illustrated embodiment, the stimulation lead 102 is a paddle leadhaving a flat paddle-shaped distal end, wherein the electrodes 116 arecarried on one side of the paddle. The electrodes 116 are arranged inthree columns along the axis of the stimulation lead 102, with theelectrodes in one lateral column (left column when lead 102 isintroduced into the patient in the rostral direction) being labeledE_(L), the electrodes in the center column being labeled E_(C), and theelectrodes in the other lateral column (right column when lead 102 isintroduced into the patient in the rostral direction) being labeledE_(R). Each row of the electrodes 116 (which includes a left electrodeE_(L), a center electrode E_(C), and a right electrode E_(R)) isarranged in a line transversely to the axis of the lead 102. The actualnumber of leads and electrodes will, of course, vary according to theintended application. In alternative embodiments, one or morepercutaneous leads with electrodes arranged in-line along the leads canbe provided.

As will be described in further detail below, the IPG 104 includes pulsegeneration circuitry that provides electrical conditioning andstimulation energy to the electrode array 116 in accordance with a setof parameters. Such parameters may comprise electrode combinations,which define the electrodes that are activated as anodes (positive),cathodes (negative), and turned off (zero), and electrical pulseparameters, which define the pulse amplitude (measured in milliamps orvolts depending on whether the IPG 104 supplies constant current orconstant voltage to the electrode array 116), pulse duration (measuredin microseconds), pulse rate (measured in pulses per second), and delaybetween stimulation and conditioning pulses (measured in microseconds).

With respect to the pulse patterns provided during operation of the SCSsystem 100, electrodes that are selected to transmit or receiveelectrical energy are referred to herein as “activated,” whileelectrodes that are not selected to transmit or receive electricalenergy are referred to herein as “non-activated.” Electrical energydelivery will occur between two (or more) electrodes, one of which maybe the IPG case, so that the electrical current has a path from theenergy source contained within the IPG case to the tissue and a returnpath from the tissue to the energy source contained within the case.Electrical energy may be transmitted to the tissue in a monopolar ormultipolar (e.g., bipolar, tripolar, etc.) fashion.

Monopolar delivery occurs when a selected one or more of the leadelectrodes 116 is activated along with the case of the IPG 104, so thatelectrical energy is transmitted between the selected electrode 116 andcase. Monopolar delivery may also occur when one or more of the leadelectrodes 116 are activated along with a large group of lead electrodes116 located remotely from the one more lead electrodes 116 so as tocreate a monopolar effect; that is, electrical energy is conveyed fromthe one or more lead electrodes 116 in a relatively isotropic manner.

Bipolar delivery occurs when two of the lead electrodes 116 areactivated as anode and cathode, so that electrical energy is transmittedbetween the selected electrodes 116. For example, the center electrodeE_(C) may be activated as an anode at the same time that the leftelectrode E_(L) is activated as a cathode. Tripolar delivery occurs whenthree of the lead electrodes 116 are activated, two as anodes and theremaining one as a cathode, or two as cathodes and the remaining one asan anode. For example, the left and right electrodes E_(L), E_(R) may beactivated as anodes at the same time that the center electrode E_(C) isactivated as a cathode.

Referring to FIG. 6, the stimulation lead 102 is implanted within thespinal column 142 of a patient 140. The preferred placement of thestimulation lead 102 is adjacent, i.e., resting upon, the spinal cordarea to be stimulated. Due to the lack of space near the location wherethe stimulation lead 102 exits the spinal column 140, the IPG 104 isgenerally implanted in a surgically-made pocket either in the abdomen orabove the buttocks. The IPG 104 may, of course, also be implanted inother locations of the patient's body. The lead extension 114facilitates locating the IPG 104 away from the exit point of thestimulation lead 102. After implantation, the IPG 104 is used to providethe therapeutic stimulation under control of the patient.

As shown in FIG. 7, a row of electrodes 116 are arranged along a linetransverse to the axis of the spinal cord SC, such that the centerelectrode E_(C) is located over the center of the dorsal column (DC)nerve fibers, and the left and right electrodes E_(L), E_(R) arelaterally placed from the center of the DC nerve fibers adjacent therespective dorsal root (DR) nerve fibers, thereby forming amedio-lateral electrode configuration. Alternatively, if a percutaneousstimulation lead is used, the electrodes of the lead can be arranged ina line along the axis of the spinal cord SC, or if multiple percutaneousstimulation leads are used, the electrodes may be arranged inunstaggered columns, such that a row of electrodes may be placed incontact with the spinal cord SC in the manner shown in FIG. 7. In a casewhere only two columns of electrodes are provided, one column ofelectrodes can be placed laterally on one side of the centerline of thespinal cord SC and the other column of electrodes can be placedlaterally on the other side of the centerline of the spinal cord SC. Inalternative embodiments, electrodes may be rostro-caudally arranged in aline parallel to the axis of the spinal cord SC.

Turning next to FIG. 8, the main internal components of the IPG 104 willnow be described. The IPG 104 includes analog output circuitry 150capable of individually generating electrical pulses of specifiedamplitude under control of control logic 152 over data bus 154. Thepulse rate and pulse width of the electrical pulses output by the IPG104 are controlled using the timer logic circuitry 156. The timer logiccircuitry 156 may have a suitable resolution, e.g., 10 μs. Theseelectrical pulses are supplied via capacitors C1-Cn to electricalcontacts 158 corresponding to electrodes E1-En and the case electrode.As will be described in further detail below, the analog outputcircuitry 150 is capable of outputting both sub-threshold conditioningpulses and stimulation pulses to the electrical contacts 158, and thus,the electrodes E1-En.

In the illustrated embodiment, the analog output circuitry 150 comprisesa plurality m independent current source pairs 160 capable of supplyingelectrical energy to the electrical contacts 158 at a specified andknown amperage. One current source 162 of each pair 160 functions as apositive (+) or anodic current source, while the other current source164 of each pair 160 functions as a negative (−) or cathodic currentsource. The outputs of the anodic current source 162 and the cathodiccurrent source 164 of each pair 160 are connected to a common node 166.The analog output circuitry 150 further comprises a low impedanceswitching matrix 168 through which the common node 166 of each currentsource pair 160 is connected to any of the electrical contacts 158 viathe capacitors C1-Cn. Alternatively, the analog output circuitry 150does not use a low impedance switching matrix 168, but rather uses abi-directional current source for each of the electrical contacts 158.

Thus, for example, it is possible to program the first anodic currentsource 162 (+I1) to produce a pulse of +4 ma (at a specified rate andfor a specified duration), and to synchronously program the secondcathodic current source 164 (−I2) to similarly produce a pulse of −4 ma(at the same rate and pulse width), and then connect the node 86 of theanodic current source 162 (+I1) to the electrical contact 158corresponding to electrode E3, and connect the node 80 of the cathodiccurrent source 164 (−I2) to the electrical contact 158 corresponding toelectrode E1.

Hence, it is seen that each of the programmable electrical contacts 158can be programmed to have a positive (sourcing current), a negative(sinking current), or off (no current) polarity. Further, the amplitudeof the current pulse being sourced or sunk from a given electricalcontact 158 may be programmed to one of several discrete levels. In oneembodiment, the current through each electrical contact 158 can beindividually set from 0 to ±10 ma in steps of 100 μa, within the outputvoltage/current requirements of the IPG 104. Additionally, in oneembodiment, the total current output by a group of electrical contacts158 can be up to ±20 ma (distributed among the electrodes included inthe group). Moreover, it is seen that each of the electrical contacts158 can operate in a multipolar mode, e.g., where two or more electricalcontacts are grouped to source/sink current at the same time.Alternatively, each of the electrical contacts 158 can operate in amonopolar mode where, e.g., the electrical contacts 158 are configuredas cathodes (negative), and case of the IPG 104 is configured as ananode (positive).

It can be appreciated that an electrical contact 158 may be assigned anamplitude and included with any of up to k possible groups, where k isan integer corresponding to the number of channels, and in preferredembodiment is equal to 4, and with each channel k having a defined pulsewidth and pulse rate. Other channels may be realized in a similarmanner. Thus, each channel identifies which electrical contacts 158 (andthus electrodes) are selected to synchronously source or sink current,the pulse amplitude at each of these electrical contacts, and the pulsewidth and pulse rate.

In an alternative embodiment, rather than using independent controlledcurrent sources, independently controlled voltage sources for providingelectrical pulses of a specified and known voltage at the electricalcontacts 158 can be provided. The operation of this output circuitry,including alternative embodiments of suitable output circuitry forperforming the same function of generating electrical pulses of aprescribed amplitude and width, is described more fully in U.S. Pat.Nos. 6,516,227 and 6,993,384, which are expressly incorporated herein byreference.

The IPG 104 further comprises monitoring circuitry 170 for monitoringthe status of various nodes or other points 172 throughout the IPG 104,e.g., power supply voltages, temperature, battery voltage, and the like.The IPG 104 further comprises processing circuitry in the form of amicrocontroller 174 that controls the control logic 152 over data bus176, and obtains status data from the monitoring circuitry 170 via databus 178. The IPG 104 additionally controls the timer logic 156. The IPG104 further comprises memory 180 and oscillator and clock circuit 182coupled to the microcontroller 174. The microcontroller 174, incombination with the memory 180 and oscillator and clock circuit 182,thus comprise a microprocessor system that carries out a programfunction in accordance with a suitable program stored in the memory 180.Alternatively, for some applications, the function provided by themicroprocessor system may be carried out by a suitable state machine.

Thus, the microcontroller 174 generates the necessary control and statussignals, which allow the microcontroller 174 to control the operation ofthe IPG 104 in accordance with a selected operating program andelectrical stimulation parameters. In controlling the operation of theIPG 104, the microcontroller 174 is able to individually generateelectrical pulses at the electrodes 116 using the analog outputcircuitry 150, in combination with the control logic 152 and timer logic156, thereby allowing each electrode 116 to be paired or grouped withother electrodes 116, including the monopolar case electrode, and tocontrol the polarity, amplitude, rate, pulse width, delay betweenconditioning pre-pulses and stimulation pulses, and channel throughwhich the current stimulus pulses are provided.

The IPG 104 further comprises an alternating current (AC) receiving coil184 for receiving programming data (e.g., the operating program and/orstimulation parameters) from the HHP 106 in an appropriate modulatedcarrier signal, and charging and forward telemetry circuitry 186 fordemodulating the carrier signal it receives through the AC receivingcoil 184 to recover the programming data, which programming data is thenstored within the memory 180, or within other memory elements (notshown) distributed throughout the IPG 104.

The IPG 104 further comprises back telemetry circuitry 188 and analternating current (AC) transmission coil 190 for sending informationaldata sensed through the monitoring circuitry 170 to the HHP 106. Theback telemetry features of the IPG 104 also allow its status to bechecked. For example, any changes made to the stimulation parameters areconfirmed through back telemetry, thereby assuring that such changeshave been correctly received and implemented within the IPG 104.Moreover, upon interrogation by the HHP 106, all programmable settingsstored within the IPG 104 may be uploaded to the HHP 106.

The IPG 104 further comprises a rechargeable power source 192 and powercircuits 194 for providing the operating power to the IPG 104. Therechargeable power source 192 may, e.g., comprise a lithium-ion orlithium-ion polymer battery. The rechargeable battery 192 provides anunregulated voltage to the power circuits 194. The power circuits 194,in turn, generate the various voltages 196, some of which are regulatedand some of which are not, as needed by the various circuits locatedwithin the IPG 104. The rechargeable power source 192 is recharged usingrectified AC power (or DC power converted from AC power through othermeans, e.g., efficient AC-to-DC converter circuits, also known as“inverter circuits”) received by the AC receiving coil 184. To rechargethe power source 192, an external charger (not shown), which generatesthe AC magnetic field, is placed against, or otherwise adjacent, to thepatient's skin over the implanted IPG 104. The AC magnetic field emittedby the external charger induces AC currents in the AC receiving coil184. The charging and forward telemetry circuitry 186 rectifies the ACcurrent to produce DC current, which is used to charge the power source192. While the AC receiving coil 184 is described as being used for bothwirelessly receiving communications (e.g., programming and control data)and charging energy from the external device, it should be appreciatedthat the AC receiving coil 184 can be arranged as a dedicated chargingcoil, while another coil, such as coil 190, can be used forbi-directional telemetry.

As shown in FIG. 8, much of the circuitry included within the IPG 104may be realized on a single application specific integrated circuit(ASIC) 198. This allows the overall size of the IPG 104 to be quitesmall, and readily housed within a suitable hermetically-sealed case.Alternatively, most of the circuitry included within the IPG 104 may belocated on multiple digital and analog dies, as described in U.S. patentapplication Ser. No. 11/177,503, filed Jul. 8, 2005, which isincorporated herein by reference in its entirety. For example, aprocessor chip, such as an application specific integrated circuit(ASIC), can be provided to perform the processing functions withon-board software. An analog IC (AIC) can be provided to perform severaltasks necessary for the functionality of the IPG 104, includingproviding power regulation, stimulus output, impedance measurement andmonitoring. A digital IC (Dig IC) may be provided to function as theprimary interface between the processor IC and analog IC by controllingand changing the levels and sequences of the current output by thestimulation circuitry in the analog IC when prompted by the processorIC.

It should be noted that the diagram of FIG. 8 is functional only, and isnot intended to be limiting. Those of skill in the art, given thedescriptions presented herein, should be able to readily fashionnumerous types of IPG circuits, or equivalent circuits, that carry outthe functions indicated and described. Additional details concerning theabove-described and other IPGs may be found in U.S. Pat. No. 6,516,227,U.S. Patent Publication No. 2003/0139781, and U.S. patent applicationSer. No. 11/138,632, entitled “Low Power Loss Current Digital-to-AnalogConverter Used in an Implantable Pulse Generator,” which are expresslyincorporated herein by reference. It should be noted that rather than anIPG, the SCS system 100 may alternatively utilize an implantablereceiver-stimulator (not shown) connected to the stimulation lead 102.In this case, the power source, e.g., a battery, for powering theimplanted receiver, as well as control circuitry to command thereceiver-stimulator, will be contained in an external controllerinductively coupled to the receiver-stimulator via an electromagneticlink. Data/power signals are transcutaneously coupled from acable-connected transmission coil placed over the implantedreceiver-stimulator. The implanted receiver-stimulator receives thesignal and generates the stimulation in accordance with the controlsignals.

As briefly discussed above, the IPG 104 (or ETS 110) is capable ofoutputting both conditioning pulses and stimulation pulses to theelectrical contacts 158, and thus, the electrodes 116 and caseelectrode. Using the electrode arrangement illustrated in FIG. 7, theIPG 104 (or ETS 110) preferentially stimulates a tissue region relativeto another tissue region, and in the illustrated case, preferentiallystimulates the DC nerve fibers, while suppressing stimulation of the DRnerve fibers. In particular, the DR nerve fibers are rendered lessexcitable to a subsequent electrical pulse by conveying a sub-thresholdconditioning pre-pulse from left and right electrodes E_(L), E_(R), andthe DC nerve fibers are subsequently stimulated by conveying astimulation pulse from the center electrode E_(C). Alternatively, theIPG 104 (or ETS 110) preferentially stimulates the DR nerve fibers,while suppressing stimulation of the DC nerve fibers. In particular, theDC nerve fibers are rendered less excitable to a subsequent electricalpulse by conveying a sub-threshold conditioning pre-pulse from thecenter electrode E_(C), and the DR nerve fibers are subsequentlystimulated by conveying stimulation pulses from left and rightelectrodes E_(L), E_(R). Any either event, the conditioning pulses andstimulation pulses may be delivered to the electrodes in a monopolarmanner, a bipolar manner, or both, as described in U.S. patentapplication Ser. No. 11/xxx,xxx (Docket No. 06-01568-01), which isexpressly incorporated herein by reference.

Notably, in the SCS context, the electrodes 116 are placed as closely aspossible to the neural tissue of the spinal cord in order to maximizethe resolution of the energy transmitted by the electrodes 116; that is,to focus the stimulating effect of the stimulation pulses on the tissueintended to be stimulated, and to focus the suppressing effect of thesub-threshold conditioning pulses on the tissue intended to besuppressed. Preferably, the proximity of the electrodes to the neuraltissue should be less than one-half of the distance between adjacentelectrodes to ensure the proper resolution. Because the electrodes 116are typically separated from the neural tissue by the dura and spinalcord fluid, there will typically be some distance between the electrodes116 and the neural tissue, with the distance varying from patient topatient. If implanted within the cervical region of the spine, theproximity of the electrodes to the neural tissue will typically be quitesmall, and therefore, high resolution can be achieved. If implantedwithin the thoracic region of the spine, the proximity of the electrodesto the neural tissue will be greater, and therefore, a lower resolutionwill be achieved.

In one embodiment illustrated in FIG. 9, each conditioning pulse takesthe form of a sub-threshold, anodic, conditioning pre-pulse 200, whichserves to hyperpolarize tissue to render it less excitable to subsequentstimulation, and the stimulation pulse takes the form of a cathodicstimulation pulse 202 that serves to depolarize the tissue to evoke anaction potential. Notably, as the duration between the conditioningpulse 200 and the stimulation pulse 202 decreases, the effect of theconditioning pulse 200 increases. As such, the duration betweenconditioning pulse 200 and stimulation pulse 202 is preferably zero, butat the least should be less than 100 μs, and more preferably, less than30 μs.

Significantly, the conditioning pre-pulse 200 has a relatively shortduration, preferably less than 200 μs, more preferably less than 150 μs,and most preferably less than 75 μs. As will be described in furtherdetail below, the conditioning pre-pulse 200 is most effective whencoupled with a relatively short duration stimulation pulse 202 (e.g., astimulation pulse having a duration less than 200 μs). In particular, incontrast to prior art tissue conditioning techniques that utilizerelatively long depolarizing pre-pulses that act predominantly on theh-gates of the sodium ion channels in the neural axons (by closing theh-gates), the use of relatively short hyperpolarizing pre-pulses actpredominantly on the m-gates of the sodium ion channels in the neuralaxons (by closing the m-gates) to render the tissue less excitable tosubsequent stimulation.

Because the conditioning pre-pulse 200 is hyperpolarizing, it also actsto open the h-gates of the sodium ion channels, but to a lesser extentsince the h-gates react more slowly than to the m-gates. That is, therelatively short duration of the hyperpolarizing pre-pulse 200 takesadvantage of the different time constants of the fast m-gates and theslow h-gates to predominantly act on the m-gates. Thus, unlike thelonger duration hyperpolarizing pre-pulses used in prior art techniques,which served to render the tissue more excitable by opening the h-gates,the relatively short duration of the hyperpolarizing pre-pulse 200serves to render the tissue less excitable by closing the m-gates.

In an optional embodiment illustrated in FIG. 10, a relatively longcathodic, conditioning, pre-pulse 204, which serves to depolarize tissueto render it less excitable to the subsequent stimulation pulse 202,precedes the short hyperpolarizing, conditioning, pre-pulse 200. In thiscase, the long depolarizing, conditioning pre-pulse 204 operates toclose the h-gates, in addition to closing of the m-gates by the shorthyperpolarizing, conditioning pre-pulse 200, thereby rendering thetissue even less excitable.

In another optional embodiment illustrated in FIG. 11, an anodic,conditioning post-pulse 206, which serves to hyperpolarize tissue,follows the stimulation pulse 202, thereby rendering the tissue evenless excitable to the stimulation, with the effect of the conditioningpost-pulse 206 increasing as the time delay between the stimulationpulse 202 and the conditioning post-pulse 206 approaches zero,preferably within 50 μs. In still another optional embodiment, ananodic, concurrent-pulse (not shown), which serves to further render thetissue less excitable to stimulation, is created. For example, theconditioning post-pulse 206 may overlap the stimulation pulse 202 intime to create the concurrent-pulse, which serves to change the field toavoid stimulation in a local region adjacent the concurrent-pulse. Or aconcurrent-pulse distinct from, and having a different amplitude levelthan, the conditioning post-pulse 206 can be created. In eitherscenario, it is preferred that the pulses be supplied by independentcurrent or voltage sources to allow the stimulation pulse 202 andpost-pulse 206 to be simultaneously created.

Notably, in any of the optional embodiments, if the hyperpolarizingconditioning pre-pulse 202 and stimulation pulse 204 are delivered totwo different tissue regions via separate electrodes (e.g., in themanner described with respect to the DR nerve fibers and DC nerve fibersillustrated in FIG. 7), the depolarizing conditioning pre-pulse 204 andthe hyperpolarizing conditioning post-pulse 206 are applied to the sametissue region as the hyperpolarizing pre-pulse 202.

For example, the hyperpolarizing conditioning pre-pulse 200, along withthe optional depolarizing conditioning pre-pulse 204 and hyperpolarizingconditioning post-pulse 206, can be conveyed from the left and rightelectrodes E_(L), E_(R) to render the DR nerve fibers less excitable tosimulation, and the stimulation pulse 202 can be conveyed from thecenter electrode E_(C) to stimulate the DC nerve fibers. Or, thehyperpolarizing conditioning pre-pulse 200, along with the optionaldepolarizing conditioning pre-pulse 204 and hyperpolarizing conditioningpost-pulse 206, can be conveyed from the center electrode E_(C) torender the DC nerve fibers less excitable to simulation, and thestimulation pulse 202 can be conveyed from the left and right electrodesE_(L), E_(R) to stimulate the DR nerve fibers.

Referring to FIG. 12, a computational model of a neural axon 210, astimulation electrode 212 that is presumably near a first tissue regionthat when stimulated yields a therapeutic effect, and a suppressionelectrode 214 that is presumably near a second tissue region that whenstimulate yields undesirable side effects, was generated to performvarious case studies described below. Thus, in this scenario, the neuralaxon 210 represents the second tissue region that yields the side effectwhen stimulated, and on which the suppression electrode 214 is used toinhibit stimulation evoked by the activity of the stimulation electrode212. The model of the neural axon 210 is an electrical network modelwith non-linear dynamics and a diameter of 10 μm. The stimulation andsuppression electrodes 212, 214 are modeled as point sourcesrespectively located 2000 μm and 100 μm from the neural axon 210. Ofcourse, other more sophisticated models that include more orientationsof nerve fibers, inhomogenous media, and finite sized electrodes, can beused.

Referring to FIGS. 13 a-13 f, a first case study was conducted by firstapplying a stimulation pulse to the stimulation electrode 212 alone(i.e., without applying a sub-threshold conditioning pre-pulse to thesuppression electrode 214) to determine the amplitude level of thestimulation pulse needed to evoke an action potential in the neural axon210, and then applying the same stimulation pulse to the stimulationelectrode 212 coupled with a sub-threshold, depolarizing, conditioningpre-pulse to the suppression electrode 214 in a prior art manner todetermine the amplitude level of the stimulation pulse needed to evokean action potential in the neural axon 210, and ultimately, to determinethe increase in the action potential threshold provided by thedepolarizing conditioning pre-pulse as a measure of its inhibitoryeffect. In this case study, both the conditioning pre-pulse and thestimulation pulse are cathodic, the stimulation pulse was selected tohave a duration of 500 μs, the conditioning pre-pulse was selected tohave a duration of 1000 μs and an amplitude level of −2.9 μA, and thedelay between the conditioning pre-pulse and stimulation pulse wasselected to be zero.

When applied alone, as shown in FIG. 13 b, the stimulation pulse wasincreased from an initial level until an action potential, asrepresented by the transmembrane voltage in FIG. 13 a, was evoked in theneural axon 210. An action potential was found to occur when theamplitude of the stimulation pulse reached −156 μA. Notably, as shown inFIG. 13 c, up until the stimulation pulse is applied (when the neuralaxon 210 is at rest), the probability of any one m-gate being open(“m-gate openness probability”) is maintained at a very low level, andthe probability of any one h-gate being open (“h-gate opennessprobability”) is maintained at a relatively high level, so that theneural axon 210 is nominally excitable to the subsequent stimulationpulse.

In contrast, when coupled with a depolarizing conditioning pre-pulse, asshown in FIG. 13 e, the amplitude of the stimulation pulse was increasedfrom an initial level until an action potential was evoked in the neuralaxon 210. An action potential was found to occur when the amplitude ofthe stimulation pulse reached −166 μA, a 6.1% increase over theamplitude required to evoke an action potential in the neural axon 210when not coupled with a conditioning pre-pulse. The transmembranevoltage representing the lack of an action potential just prior to thestimulation pulse reaching −166 μA is shown in FIG. 13 d. Notably, asshown in FIG. 13 f, the application of the conditioning pre-pulserapidly increases the m-gate openness probability, while slowlydecreasing the h-gate openness probability. While increasing the m-gateopenness probability initially renders the neural axon 210 moreexcitable at the beginning of the conditioning pulse, the eventualdecrease in the h-gate openness probability renders the neural axon 210less excitable to the subsequently applied stimulation pulse. Thus, aspreviously described in the background, the use of a long duration,depolarizing, conditioning pulse predominantly operates on the h-gatesto render the neural axon 210 less excitable to subsequent stimulation.

Referring to FIGS. 14 a-14 f, a second case study was conducted in thesame manner as the first case study, with the exception that thestimulation pulse was decreased to a 200 μs duration, and the amplitudeof the conditioning pulse was selected to be −2 μA. When applied alone,as shown in FIG. 14 b, the amplitude of the stimulation pulse wasincreased from an initial level until an action potential, asrepresented by the transmembrane voltage in FIG. 14 a, was evoked in theneural axon 210. An action potential was found to occur when theamplitude of the stimulation pulse reached −243 μA. In a manner similarto the first case study, up until the stimulation pulse is applied (whenthe neural axon 210 is at rest), the m-gate openness probability ismaintained at a very low level, and the h-gate openness probability ismaintained at a very high level, as illustrated in FIG. 14 c, so thatthe neural axon 210 is nominally excitable to the subsequent stimulationpulse.

In contrast, when coupled with the depolarizing conditioning pre-pulse,as shown in FIG. 14 e, the amplitude of the stimulation pulse wasincreased from an initial level until an action potential was evoked inthe neural axon 210. An action potential was found to occur when theamplitude of the stimulation pulse reached −245 μA, only a 0.8% increaseover the amplitude required to evoke an action potential in the neuralaxon 210 when not coupled with a conditioning pre-pulse. Thetransmembrane voltage representing the lack of an action potential justprior to the stimulation pulse reaching −245 μA is shown in FIG. 14 d.Notably, as shown in FIG. 14 f, the use of a long duration,depolarizing, conditioning pulse predominantly operates on the h-gatesto render the neural axon 210 less excitable to the subsequently appliedstimulation pulse. However, due to the shortening of the stimulationpulse duration, the effect of the conditioning pre-pulse illustrated inFIG. 14 e is minimal. Significantly, the effectiveness of thisconditioning pre-pulse would be even more diminished at much lowerstimulation pulse durations (e.g., 50 μs).

Referring to FIGS. 15 a-15 f, a third case study was conducted in thesame manner as the first case study, with the exception that asub-threshold, hyperpolarizing, conditioning pre-pulse, instead of asub-threshold, depolarizing, conditioning pre-pulse, was used. In thiscase study, the conditioning pre-pulse is anodic, and the stimulationpulse is cathodic, the stimulation pulse was selected to have a durationof 50 μs, the conditioning pre-pulse was selected to have a duration of50 μs and an amplitude level of 30 μA, and the delay between theconditioning pre-pulse and the stimulation pulse was selected to bezero.

When applied alone, as shown in FIG. 15 b, the amplitude of thestimulation pulse was increased from an initial level until an actionpotential, as represented by the transmembrane voltage in FIG. 15 a, wasevoked in the neural axon 210. An action potential was found to occurwhen the amplitude of the stimulation pulse reached −628 μA. In a mannersimilar to the first case study, up until the stimulation pulse isapplied (when the neural axon 210 is at rest), the m-gate opennessprobability is maintained at a very low level, and the h-gate opennessprobability is maintained at a very high level, as illustrated in FIG.15 c, so that the neural axon 210 is nominally excitable to thesubsequent stimulation pulse.

In contrast, when coupled with a hyperpolarizing conditioning pre-pulse,as shown in FIG. 15 e, the amplitude of the stimulation pulse wasincreased from an initial level until an action potential was evoked inthe neural axon 210. An action potential was found to occur when theamplitude of the stimulation pulse reached −702 μA, an 11.7% increaseover the amplitude required to evoke an action potential in the neuralaxon 210 when not coupled with a conditioning pre-pulse. Notably, theuse of this hyperpolarizing, conditioning, pre-pulse increased thethreshold of the neural axon 210 twice as much as the long duration,depolarizing condition pre-pulse did in the first case study. Thetransmembrane voltage representing the lack of an action potential justprior to the stimulation pulse reaching −702 μA is shown in FIG. 15 d.Notably, as shown in FIG. 15 f, the application of the conditioningpre-pulse decreases the m-gate openness probability. Significantly, dueto the relatively short duration of the conditioning pre-pulse, theh-gate openness probability is not drastically affected. That is,because the h-gates have a higher time constant than do the m-gates, theuse of a short duration, hyperpolarizing, conditioning pulsepredominantly operates on the m-gates to render the neural axon 210 lessexcitable to the subsequently applied stimulation pulse. Notably,although the time constant differences between the h-gates and m-gatesare difficult to see in FIG. 15 f due to scaling, a close-up of FIG. 15f would reveal that the h-gate openness probability increases well afterthe m-gate openness probability increases.

Referring to FIGS. 16 a-16 c, a fourth case study was conducted in thesame manner as the third case study, with the exception that asub-threshold, hyperpolarizing, conditioning post-pulse was used inaddition to the hyperpolarizing, conditioning pre-pulse. In this casestudy, the conditioning post-pulse is anodic, the conditioningpost-pulse was selected to have a duration of 250 μs and an amplitudelevel of 2.5 μA, and the delay between the stimulation pulse and theconditioning post-pulse was selected to be zero.

When coupled with a hyperpolarizing conditioning pre-pulse and ahyperpolarizing conditioning post-pulse, as shown in FIG. 16 b, theamplitude of the stimulation pulse was increased from an initial leveluntil an action potential was evoked in the neural axon 210. An actionpotential was found to occur when the amplitude of the stimulation pulsereached −743 μA, an 18.3% increase over the amplitude required to evokean action potential in the neural axon 210 when not coupled with aconditioning pre-pulse and conditioning post-pulse. The transmembranevoltage representing the lack of an action potential just prior to thestimulation pulse reaching −743 μA is shown in FIG. 16 a. Notably, asshown in FIG. 16 c, the application of the conditioning post-pulsedecreases the m-gate openness probability after the stimulation pulse isapplied to render the neural axon 210 even less excitable to thepreviously applied stimulation pulse. Notably, as shown in FIG. 16 c,the m-gates have a rebound-opening effect at the end of the conditioningpost-pulse, suggesting that a post-pulse that tapers in time may be moreeffective than a post-pulse ending in a strong discontinuity.

Referring to FIGS. 17 a-17 c, a fifth case study was conducted in thesame manner as the fourth case study, with the exception that theconditioning post-pulse overlaps the stimulation pulse by 100 μs. Thatis, the initial portion of the post-pulse is actually a concurrentconditioning pulse. As shown in FIG. 17 b, the amplitude of thestimulation pulse was increased from an initial level until an actionpotential was evoked in the neural axon 210. An action potential wasfound to occur when the amplitude of the stimulation pulse reached −782μA, a 24.5% increase over the amplitude required to evoke an actionpotential in the neural axon 210 when not coupled with a conditioningpre-pulse and conditioning post-pulse. The transmembrane voltagerepresenting the lack of an action potential just prior to thestimulation pulse reaching −782 μA is shown in FIG. 17 a. Notably, asshown in FIG. 17 c, the application of the conditioning concurrent pulsedecreases the m-gate openness probability during application of thestimulation pulse (i.e., during the last 100 μs of the stimulationpulse), and the application of the conditioning concurrent-pulse andpost-pulse decreases the m-gate openness probability after thestimulation pulse is applied, to render the neural axon 210 even lessexcitable to the stimulation pulse.

Although particular embodiments of the present inventions have beenshown and described, it will be understood that it is not intended tolimit the present inventions to the preferred embodiments, and it willbe obvious to those skilled in the art that various changes andmodifications may be made without departing from the spirit and scope ofthe present inventions. Thus, the present inventions are intended tocover alternatives, modifications, and equivalents, which may beincluded within the spirit and scope of the present inventions asdefined by the claims.

1. (canceled)
 2. A neurostimulation system, comprising: a plurality ofelectrical contacts; analog output circuitry capable of outputtingelectrical pulses to the plurality of electrical contacts in accordancewith a pulse pattern; and control circuitry capable of defining thepulse pattern, such that the electrical pulses comprise a sub-threshold,conditioning, pre-pulse outputted to a first one of the electricalcontacts, and a stimulation pulse outputted to a second different one ofthe electrical contacts, wherein the conditioning pre-pulse has aduration less than 200 μs and is equal to or shorter than thestimulation pulse.
 3. The neurostimulation system of claim 2, whereinthe conditioning pulse is anodic, and the depolarizing stimulation pulseis cathodic.
 4. The neurostimulation system of claim 2, wherein theconditioning pre-pulse has a duration equal to or less than 150 μs. 5.The neurostimulation system of claim 2, wherein the conditioningpre-pulse has a duration equal to or less than 75 μs.
 6. Theneurostimulation system of claim 2, wherein the stimulation pulse has aduration less than 200 μs.
 7. The neurostimulation system of claim 2,wherein the control circuitry is capable of defining the pulse pattern,such that the electrical pulses further comprise a sub-threshold,conditioning, post-pulse outputted to the first one of the electricalcontacts.
 8. The neurostimulation system of claim 2, wherein theconditioning post-pulse overlaps the stimulation pulse in time.
 9. Theneurostimulation system of claim 8, further comprising one or morestimulation leads carrying a plurality of electrodes in electricalcommunication with the plurality of electrical contacts.
 10. Theneurostimulation system of claim 9, wherein the one or more stimulationleads comprises one or more spinal cord stimulation leads.
 11. Theneurostimulation system of claim 2, further comprising memory capable ofstoring a set of stimulation parameters, wherein the control circuitryis capable of defining the pattern in accordance with the stimulationparameter set.
 12. The neurostimulation system of claim 2, furthercomprising a case, wherein the plurality of electrical contact, analogoutput circuitry, and control circuitry are contained in the case toform a an implantable neurostimulator.